In:
American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society, Vol. 297, No. 5 ( 2009-11), p. L892-L902
Abstract:
Exposure to cigarette smoke extract (CSE) leads to airway or lung inflammation, which may be mediated through cyclooxygenase-2 (COX-2) expression and its product prostaglandin E 2 (PGE 2 ) synthesis. The aim of this study was to investigate the molecular mechanisms underlying CSE-induced COX-2 expression in human tracheal smooth muscle cells (HTSMCs). Here, we describe that COX-2 induction is dependent on PKCα/c-Src/EGFR, PDGFR/PI3K/Akt/NF-κB signaling in HTSMCs. CSE stimulated the phosphorylation of c-Src, EGFR, PDGFR, and Akt, which were inhibited by pretreatment with the inhibitor of PKCα (Gö6976 or Gö6983), c-Src (PP1), EGFR (AG1478), PDGFR (AG1296), or PI3K (LY294002). Moreover, CSE induced a significant increase in COX-2 expression, which was reduced by pretreatment with these inhibitors or transfection with siRNA of PKCα, Src, or Akt. Furthermore, CSE-stimulated NF-κB p65 phosphorylation and translocation were also attenuated by pretreatment with Gö6976, PP1, AG1478, AG1296, or LY294002. CSE-induced COX-2 expression was also mediated through the recruitment of p300 associated with NF-κB in HTSMCs, revealed by coimmunoprecipitation and Western blot analysis. In addition, pretreatment with the inhibitors of NF-κB (helenalin) and p300 (garcinol) or transfection with p65 siRNA and p300 siRNA markedly inhibited CSE-regulated COX-2 expression. However, CSE-induced PGE 2 generation was reduced by pretreatment with the inhibitor of COX-2 (NS-398). These results demonstrated that in HTSMCs, CSE-induced COX-2-dependent PGE 2 generation was mediated through PKCα/c-Src/EGFR, PDGFR/PI3K/Akt leading to the recruitment of p300 with NF-κB complex.
Type of Medium:
Online Resource
ISSN:
1040-0605
,
1522-1504
DOI:
10.1152/ajplung.00151.2009
Language:
English
Publisher:
American Physiological Society
Publication Date:
2009
detail.hit.zdb_id:
1013184-X
detail.hit.zdb_id:
1477300-4
SSG:
12
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